Background: Adverse neurodevelopmental outcome after preterm birth is strongly associated with a phenotype that combines: cognitive dysfunction and special educational needs; altered early brain growth; and cerebral white matter injury. This is only partly explained by environmental stresses. Based on studies of the imaging and clinical phenotype we hypothesized that the development of preterm cerebral injury could be related to selected genes involved in white matter development or human cognition and behaviour.

Methods: We collected genomic DNA and magnetic resonance (MR) images from 83 preterm infants. NRES approval was obtained. Genotyping was performed using the Sequenom i-PLEX assay and MALDI-TOF mass spectrometry. Images were acquired at mean postmenstrual age 40+2 weeks. We used Tract Based Spatial Statistics (TBSS) and Deformation Based Morphometry (DBM) to examine the risks conferred by carriage of particular alleles at tag single nucleotide polymorphisms (SNPs) in a restricted number of genes and related these to the preterm cerebral endophenotype. Type 1 error was controlled using the q-value algorithm (false discovery rate 0.05)
(1).

Results: Thirty-five tag SNPs across 13 genes were tested. After correcting for prematurity and age at scan, we found that carriage of the minor allele (G) at rs2518824 in the armadillo repeat gene deleted in velocardiofacial syndrome (ARVCF) gene, which has been linked to neuronal migration and schizophrenia, was associated with reduced FA in the corpus callosum, the superior corona radiata, the fornix, and the centrum semiovale (p=0.0009). Carriage of the minor allele (A) at rs174576 in the fatty acid desaturase 2 (FADS2) gene, which encodes a rate-limiting enzyme for endogenous long chain polyunsaturated fatty acid synthesis and has been linked to intelligence, was associated with reduced FA in the corona radiata (p=0.0019). None of the remaining 33 tag SNPs were associated with FA changes after correction for multiple tests.
SNP associated alterations in tract microstructure identified in TBSS analyses were not associated with alterations in brain morphology assessed by automatic segmentation of tissue compartments.

Conclusion: These results suggest that: genetic variants modulate white matter injury after preterm birth; and known susceptibilities to neurological status in later life may be exposed by the stress of premature exposure to the extra-uterine environment.